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Summary

Humans vary in their susceptibility to the adverse effects of toxic chemicals found at Superfund sites, and a genetic component is strongly suspected. The overall goal of this project is to identify genetic factors which contribute to human susceptibility to toxicity as a result of exposure to chemicals present at Superfund sites. The application of whole genome association studies, which assess the association of single nucleotide polymorphisms with phenotypic effects of exposure on an unbiased genome-wide scale, is often precluded by the limited size of the exposed study populations. Very large numbers of individuals are required to observe true associations because of the need for multiple test correction. The candidate gene approach can be informative for smaller study populations but requires prior knowledge of the genes involved in the human response to toxicants for selection of candidate genes. As limited information is available on genes involved in the human response to many of the Superfund chemicals, the researchers developed a functional screening approach that takes advantage of the conservation of fundamental cellular processes and metabolism between yeast (S. cerevisiae) and human, to help identify candidate genes involved in human susceptibility to Superfund chemicals. In this approach, genes are selected in a yeast parallel deletion (PDA) assay by their ability to alter resistance to toxicant exposures. The roles of the selected genes are then further assessed in human and other mammalian cells in vitro. In the last project period, the researchers successfully identified a list of genes most likely to play key roles in human susceptibility to several metals, arsenicals and metabolites of benzene and trichloroethylene, through this functional screening approach. They also obtained preliminary data on the potential functions of several genes in human cells and continue expand these functional studies in human cells in vitro and in whole animal studies in vivo. In addition, the researchers are extending their yeast functional screening assay to several persistent bio-accumulative halogenated toxicants of emerging concern at Superfund sites. Further, the researchers are applying a novel and complementary human haploid cell screening approach to identify additional candidate human susceptibility genes. Together, these studies provide a comprehensive high-throughput approach to identify important genes and cellular processes involved in toxicant susceptibility.